Pharmacogenetic effect of an endothelin-1 haplotype on response to bucindolol therapy in chronic heart failure.
BACKGROUND
Beta-blocker therapy has become a mainstay therapy for the over 5 million patients with chronic heart failure in the United States. Variation in clinical response to beta-blockers is a well-known phenomenon and may be because of genetic differences between patients. We hypothesized that variation in genes of the endothelin system mediate the clinical response to beta-blockers in heart failure.


METHODS
Single nucleotide polymorphisms (SNPs) in six endothelin system genes were genotyped in 309 heart failure patients in a randomized trial of bucindolol versus placebo therapy. We adjusted for multiple comparisons and tested for association between genotype and time to two prospective endpoints.


RESULTS
Nine SNPs were sufficiently common to undergo statistical analysis. The SNPs had no significant effect on prospective outcomes in the placebo group, or on the primary endpoint of time to death in either arm. Two SNPs (IVS-4 G/A and Lys198Asn) in the endothelin-1 gene, however, predicted time to the combined endpoint of heart failure hospitalization or all-cause death in bucindolol-treated patients. The alleles at these SNPs were in tight linkage disequilibrium appearing on either of two complementary haplotypes. A 'dose-response' trend was observed, with participants carrying the rarer haplotype having the highest hazard ratios as compared to the relative 'protective' effect of the common haplotype.


CONCLUSIONS
A common endothelin-1 gene haplotype may be a pharmacogenetic predictor of a favorable clinical response to beta-blocker therapy in heart failure patients. The existence of a less common 'high-risk' haplotype could identify a subpopulation of heart failure patients destined to respond poorly to beta-blocker therapies.
Taylor
Matthew R G
MR
University of Colorado Denver, Aurora, CO, USA. matthew.taylor@ucdenver.edu
Slavov
Dobromir
D
Humphrey
Kurt
K
Zhao
Lan
L
Cockroft
Jennifer
J
Zhu
Xiao
X
Lavori
Philip
P
Bristow
Michael R
MR
Mestroni
Luisa
L
Lazzeroni
Laura C
LC
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics; D008875:Middle Aged; D008957:Models, Genetic; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011412:Propanolamines / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D017466:Receptors, Endothelin / Q000235:genetics
D000319:Adrenergic beta-Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011412:Propanolamines; D017466:Receptors, Endothelin; C024307:bucindolol; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes